SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

Generation of Priority Research Questions to Inform Conservation Policy and Management at a National Level

Integrating knowledge from across the natural and social sciences is necessary to effectively address societal tradeoffs between human use of biological diversity and its preservation. Collaborative processes can change the ways decision makers think about scientific evidence, enhance levels of mutual trust and credibility, and advance the conservation policy discourse. Canada has responsibility for a large fraction of some major ecosystems, such as boreal forests, Arctic tundra, wetlands, and temperate and Arctic oceans. Stressors to biological diversity within these ecosystems arise from activities of the country's resource-based economy, as well as external drivers of environmental change. Effective management is complicated by incongruence between ecological and political boundaries and conflicting perspectives on social and economic goals. Many knowledge gaps about stressors and their management might be reduced through targeted, timely research. We identify 40 questions that, if addressed or answered, would advance research that has a high probability of supporting development of effective policies and management strategies for species, ecosystems, and ecological processes in Canada. A total of 396 candidate questions drawn from natural and social science disciplines were contributed by individuals with diverse organizational affiliations. These were collaboratively winnowed to 40 by our team of collaborators. The questions emphasize understanding ecosystems, the effects and mitigation of climate change, coordinating governance and management efforts across multiple jurisdictions, and examining relations between conservation policy and the social and economic well-being of Aboriginal peoples. The questions we identified provide potential links between evidence from the conservation sciences and formulation of policies for conservation and resource management. Our collaborative process of communication and engagement between scientists and decision makers for generating and prioritizing research questions at a national level could be a model for similar efforts beyond Canada

Les terres agricoles face à l’urbanisation

La perte de terres agricoles liées à l’urbanisation constitue l’une des facettes de la consommation des terres. Commencé dans les années 1970, ce phénomène — essentiellement dû à l’étalement urbain — prend des proportions jusque-là inégalées. Les conséquences de ces processus d’artificialisation sont multiples et portent à la fois sur la production et sur la sécurité alimentaire ainsi que sur la perte de biodiversité. Ces processus interrogent aussi les formes de solidarité territoriale entre les villes et les espaces péri-urbains et ruraux. Issu d’une collaboration scientifique lancée au début des années 2010 entre l’Université de technologie de Sydney (University of Technology Sydney, UTS) et l’Institut national de recherche en sciences et technologies pour l’environnement et l’agriculture (Irstea), cet ouvrage aborde des points clés de la problématique de la consommation des terres en se focalisant sur les terres agricoles en France et en Australie. Plutôt que d’offrir une analyse comparative approfondie de la planification des terres agricoles périurbaines entre les deux pays, il propose une exploration des « boîtes à outils » de l’ingénierie territoriale développées et mobilisées pour faire face à l’enjeu de la perte de terres agricoles liée à l’urbanisation. Il offre également un « arrêt sur image » dans un panorama de champs de recherche en pleine évolution, autant du point de vue théorique que méthodologique

Selective breeding of <em>Saccharomyces cerevisiae</em> to increase glycerol levels in wine

Glycerol in wines is at levels of 1 to 10 g/l and improves their body. To breed wine yeast for increased glycerol production, we crossed yeast isolated from natural fermentations with a commercial strain. The average glycerol concentration of 187 wine yeast strains was 4.2 g/l. Strain Ba25 had the highest glycerol production and a spore clone of Ba25 was crossed with one of Premier Cuvée, the best commercial strain, by spore-spore pairing and this was repeated three times. Several of the spore clones produced >15 g/l of glycerol. Glycerol and ethanol levels were inversely related

Metabolic Control Analysis of Glycerol Synthesis in Saccharomyces cerevisiae

Glycerol, a major by-product of ethanol fermentation by Saccharomyces cerevisiae, is of significant importance to the wine, beer, and ethanol production industries. To gain a clearer understanding of and to quantify the extent to which parameters of the pathway affect glycerol flux in S. cerevisiae, a kinetic model of the glycerol synthesis pathway has been constructed. Kinetic parameters were collected from published values. Maximal enzyme activities and intracellular effector concentrations were determined experimentally. The model was validated by comparing experimental results on the rate of glycerol production to the rate calculated by the model. Values calculated by the model agreed well with those measured in independent experiments. The model also mimics the changes in the rate of glycerol synthesis at different phases of growth. Metabolic control analysis values calculated by the model indicate that the NAD(+)-dependent glycerol 3-phosphate dehydrogenase-catalyzed reaction has a flux control coefficient (Cv1J) of approximately 0.85 and exercises the majority of the control of flux through the pathway. Response coefficients of parameter metabolites indicate that flux through the pathway is most responsive to dihydroxyacetone phosphate concentration (RDHAPJ = 0.48 to 0.69), followed by ATP concentration (RATPJ = −0.21 to −0.50). Interestingly, the pathway responds weakly to NADH concentration (RNADHJ = 0.03 to 0.08). The model indicates that the best strategy to increase flux through the pathway is not to increase enzyme activity, substrate concentration, or coenzyme concentration alone but to increase all of these parameters in conjunction with each other

Compatible Solutes Protect against Chaotrope (Ethanol)-Induced, Nonosmotic Water Stress

Water stress is one of the major stresses experienced by cellular systems and can take a number of distinct forms. In response to turgor-related osmotic stress, cells produce compatible solutes that are macromolecule protectants and also counteract the outflow of water from stressed cells. In this report we show that the germination of conidia of Aspergillus nidulans, a sensitive indicator of water stress, in the presence of ethanol is correlated with the intracellular concentration of the compatible solutes glycerol and erythritol, which protect against both osmotic and nonturgor forms of water stress